Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation

• Published in: American journal of physiology. Lung cellular and molecular physiology 2012-12, Vol.303 (11), p.L939-L952
• Main Authors: Possa, Samantha Souza, Charafeddine, Homar Toledo, Righetti, Renato Fraga, da Silva, Patricia Angeli, Almeida-Reis, Rafael, Saraiva-Romanholo, Beatriz Mangueira, Perini, Adenir, Prado, Carla Máximo, Leick-Maldonado, Edna Aparecida, Martins, Milton A, Tibério, Iolanda de Fátima Lopes Calvo
• Format: Article
• Language: English
• Subjects: Airway management; Airway Remodeling - drug effects; Airway Resistance - drug effects; Amides - pharmacology; Amides - therapeutic use; Animals; Anti-Asthmatic Agents - pharmacology; Anti-Asthmatic Agents - therapeutic use; Asthma - drug therapy; Asthma - immunology; Asthma - metabolism; Asthma - physiopathology; Collagen - metabolism; Cytokines; Dinoprost - analogs & derivatives; Dinoprost - metabolism; Drug Evaluation, Preclinical; Elastic Tissue - metabolism; Elasticity; Eosinophils - immunology; Eosinophils - pathology; Eosinophils - physiology; Extracellular Matrix - metabolism; Guinea Pigs; Inhalation - drug effects; Interleukin-2 - metabolism; Kinases; Lung - drug effects; Lung - immunology; Lung - pathology; Male; Matrix Metalloproteinase 9 - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Oxidative stress; Oxidative Stress - drug effects; Pyridines - pharmacology; Pyridines - therapeutic use; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; Smooth muscle
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00034.2012

Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. The treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E(NO)) was collected. The lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E(NO) concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-β, NF-κB, IFN-γ, and 8-iso-prostaglandin F2α contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. In conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma.